Cases Of Ataxia Research Articles

Thermodynamic and kinetic stability of the Josephin Domain closed arrangement: evidences from replica exchange molecular dynamics

BackgroundMolecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action.ResultsConformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate/open states was characterized by a rate constant higher than 700 ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds.ConclusionThis work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date.ReviewersThis article was reviewed by Oliviero Carugo, Bojan Zagrovic.

Analysis of Genetic Mutations in a Cohort of Hereditary Optic Neuropathy in Shanghai, China.

Purpose To evaluate the clinical classification and characteristics of hereditary optic neuropathy patients in a single center in China. Method Retrospective case study. Patients diagnosed with hereditary optic neuropathy between January 2014 and December 2015 in the neuro-ophthalmology division in Shanghai Eye and ENT Hospital of Fudan University were recruited. Clinical features as well as visual field, brain/orbital MRI, and spectrum domain optical coherence tomography (SD-OCT) were analyzed. Results Eighty-two patients diagnosed by gene test were evaluated, including 66 males and 16 females. The mean age of the patients was 19.4 years (range, 5–46 years). A total of 158 eyes were analyzed, including 6 unilateral, 61 bilateral, and 15 sequential. The median duration of the disease was 0.5 year (range, 0.1–20 years). Genetic test identified 68 patients with Leber hereditary optic neuropathy, 9 with dominant optic neuropathy, and 2 with a Wolfram gene mutation. There was also one case of hereditary spastic paraplegia, spinocerebellar ataxia, and polymicrogyria with optic nerve atrophy, respectively. Conclusion Leber hereditary optic neuropathy is the most common detected type of hereditary optic neuropathy in Shanghai, China. The detection of other autosomal mutations in hereditary optic neuropathy is limited by the currently available technique.

Fourteen Years of Experience of Liver Transplantation for Wilson’s Disease; a Report on 107 Cases from Shiraz, Iran

Background and AimLiver transplantation is a potential cure for liver damage from Wilson’s disease but the course of neuropsychiatric manifestations after transplantation remains undetermined.Material and methodsIn this study, data on all patients who’d received a liver transplant for Wilson’s disease at the Shiraz Organ Transplantation Center between December 2000 and March 2014 were reviewed and compared to data on a control group who’d received a liver transplant over the same period but due to other causes.ResultsOut of 2198 patients who’d received a liver transplant in the period; 107 patients were diagnosed with Wilson’s disease (21 with fulminant hepatic failure); age of patient ranged from 5 to 59 years; 56.07% of patients in this series had some type of neuropsychiatric manifestation before transplantation, of which 66.67% showed improvement after the procedure. 18 patients had aggravation of neuropsychiatric symptoms after transplantation. These neuropsychiatric symptoms were mostly for anxiety, tremor and depression but there were four cases of new onset dysarthria, rigidity and ataxia in various combinations. Survival rates of 1-month, 1-year, and 5-years for patients with Wilson’s disease were 88%, 86%, 82%, respectively, evaluations were not statistically different from that of the control group.ConclusionsLiver transplantation showed good long-term results in patients with Wilson’s disease, even in those presenting fulminant hepatic failure. Neuropsychiatric manifestations normally show improvement after transplantation but in some cases new onset of manifestations occurred after successful liver transplantation.

Genome-wide association study for hereditary ataxia in the Parson Russell Terrier and DNA-testing for ataxia-associated mutations in the Parson and Jack Russell Terrier.

BackgroundSpinocerebellar ataxia also referred to as hereditary ataxia comprises different forms of progressive neurodegenerative diseases. A complex mode of inheritance was most likely in Parson Russell Terriers (PRT) and in Jack Russell Terriers (JRT). Recently, the missense mutation KCNJ10:c.627C > G was shown to be associated with the spinocerebellar ataxia (SCA) in JRT and related Russell group of terriers, whereas the missense mutation CAPN1:c.344G > A was associated with late onset ataxia (LOA) in PRT.ResultsWe performed a genome-wide association study (GWAS) in PRT including 15 cases and 29 controls and found a statistically strong signal in the genomic region on dog chromosome 38 (CFA38) where KCNJ10 is located. We tested the CAPN1:c.344G > A and KCNJ10:c.627C > G (Transcript XM_545752.4) mutations in a sample of 77 PRT and 9 JRT from Germany as well as further 179 controls from 20 different dog breeds. All cases and controls genotyped carried the wild-type for the CAPN1:c.344G > A mutation. Among the PRT, 17/77 (22.1 %) dogs were homozygous for the mutant KCNJ10 allele and 22/77 (28.6 %) dogs were heterozygous. Three cases of PRT had the homozygous KCNJ10 wild-type. In JRT, 1/3 cases did show the mutant KCNJ10 allele homozygous. Thus, we sequenced the KCNJ10 exons with their adjacent regions from 10 PRT and 3 JRT including the animals with imperfect co-segregation of the c.627C > G mutation. We identified a total of 45 genetic variants within KCNJ10. The most likely variant explaining the cases appeared a 1-bp-insertion in a C-stretch within exon 3 (KCNJ10:g.22141027insC). In silico analysis showed that this indel may influence the regulation of gene expression.ConclusionsIn the present study, 16/21 cases of hereditary ataxia perfectly co-segregated with the KCNJ10:c.627C > G mutation. The CAPN1:c.344G > A mutation could not be validated and seems to be a rare variant in the samples screened. Screening KCNJ10 for further mutations did result in a genetic variant explaining 2 JRT cases but further 3 cases with a non-mutant homozygous c.627C > G genotype could not be resolved. Breeders have to be aware that DNA-testing for hereditary ataxia in PRT and JRT does not capture all cases of hereditary ataxia in these dog breeds. At least one further form of hereditary ataxia not yet resolved by a mutation may occur in PRT and JRT.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0862-x) contains supplementary material, which is available to authorized users.

Purkinje cell injury, structural plasticity and fusion in patients with Friedreich's ataxia.

Purkinje cell pathology is a common finding in a range of inherited and acquired cerebellar disorders, with the degree of Purkinje cell injury dependent on the underlying aetiology. Purkinje cells have an unparalleled resistance to insult and display unique regenerative capabilities within the central nervous system. Their response to cell injury is not typical of most neurons and likely represents both degenerative, compensatory and regenerative mechanisms. Here we present a pathological study showing novel and fundamental insights into Purkinje cell injury, remodelling and repair in Friedreich’s ataxia; the most common inherited ataxia. Analysing post-mortem cerebellum tissue from patients who had Friedreich's ataxia, we provide evidence of significant injury to the Purkinje cell axonal compartment with relative preservation of both the perikaryon and its extensive dendritic arborisation. Axonal remodelling of Purkinje cells was clearly elevated in the disease. For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell’s unique plasticity and regenerative potential. Elucidating the biological mechanisms behind these phenomena could have significant clinical implications for manipulating neuronal repair in response to neurological injury.

Male tick bite: A rare cause of adult tick paralysis.

Tick paralysis is caused by a neurotoxin produced in the tick's salivary gland.1 It has been described to occur when a gravid female tick transmits the neurotoxin during feeding.2 Typically, ascending weakness begins within 2 to 7 days, which may lead to respiratory failure and death. Rarely, acute ataxia without paralysis is the presenting symptom.3 Herein, we describe a case of acute-onset ataxia and tremulousness from the bite of a male tick.

Treatment of a case of ataxia and pyramidal tract sign positive contact with the organic solvent

Treatment of a case of ataxia and pyramidal tract sign positive contact with the organic solvent

Novel CACNB4 Variant Associated with a Case of Progressive Ataxia (P5.391)

Novel CACNB4 Variant Associated with a Case of Progressive Ataxia (P5.391)

Cerebellar Ataxia, An Unusual Neurological Manifestation of Coeliac Disease- A Case Study

Coeliac disease was considered as a gluten sensitive enteropathy but now due to its wide clinical presentation is considered as multisystem autoimmune disorder. Ataxia with peripheral neuropathy is a rare manifestation of gluten sensitivity. The presence of glutenrelated immune markers in normal population however complicates the reliable diagnosis of gluten related neurological disorders and clinical improvement on gluten free diet can serve as a diagnostic tool for this disease. We report a case of sporadic progressive cerebellar ataxia with peripheral neuropathy with positive anti tissue transglutaminase (antitTG) antibodies and subtotal villous atrophy in duodenal biopsy. This case highlights an important diagnostic and therapeutic principle in management of late onset idiopathic ataxia.
 Bangladesh Journal of Neuroscience 2016; Vol. 32 (1): 43-46

A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia.

Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive condition that is caused by a mutation in the alpha tocopherol transfer protein gene. It is almost indistinguishable clinically from Friedreich's ataxia but with appropriate treatment its devastating neurological features can be prevented. Patients can present with a progressive cerebellar ataxia, pyramidal spasticity, and evidence of a neuropathy with absent deep tendon reflexes. It is important to screen for this condition on initial evaluation of a young patient presenting with progressive ataxia and it should be considered in patients with a long standing ataxia without any diagnosis in view of the potential therapeutics and genetic counselling. In this case report we present a patient who was initially diagnosed with Friedreich's ataxia but was later found to have AVED.

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In Quebec, a significant number of patients affected with cerebellar ataxia and spasticity remain without a molecular diagnosis. We performed whole-exome sequencing in three French Canadian (FC) patients affected with spastic ataxia and uncovered compound heterozygous variants in SPG7 in all three. Sanger sequencing of SPG7 exons and exon/intron boundaries was used to screen additional patients. In total, we identified recessive variants in SPG7 in 22 FC patients belonging to 12 families (38.7% of the families screened), including two novel variants. The p.(Ala510Val) variant was the most common in our cohort. Cerebellar features, including ataxia, were more pronounced than spasticity in this cohort. These results strongly suggest that variants affecting the function of SPG7 are the fourth most common form of recessive ataxia in FC patients. Thus, we propose that SPG7 mutations explain a significant proportion of FC spastic ataxia cases and that this gene should be considered in unresolved patients.

神経節神経腫による傍腫瘍症候群 (抗GluRε2抗体陽性) と考えられた反復性小脳失調症の1例

神経節神経腫による傍腫瘍症候群 (抗GluRε2抗体陽性) と考えられた反復性小脳失調症の1例

A case report: cerebellar ataxia associated to parvovirus b19

Human parvovirus B19 (PVB19) is well known to cause erythema infectiosum and has other pathological manifestations such as central nervous system (CNS) diseases, aplastic crisis, thrombocytopenia, purpura, myocarditis, and arthritis. Meningitis and encephalitis have been reported in association with this viral infection, but acute cerebellar ataxia has rare previously been documented. We report a 2 year old boy admitted acute cerebellar ataxia in association with erythematous skin lesion. He was diagnosed as human parvovirus B19 after serological tests. İn his physical examination we remarked ataxic gait, nystagmus and erytematous lesions on body. İn the 3rd day, ıdiopathic thrombocytopenic purpura was developed. All laboratuary findings were normal except thrombocytopenia. He had normal cranial MR imaging. Serology was positive for antibodies to IgM and IgG antibodies against PVB19 in blood and cerebrospinal fluid. Ataxia and nystagmus disappeared in a week without any spesific treatment. Acute cerebellar ataxia occurs in association with various viral and non-viral infections and vaccines. It has been assumed that most acute cerebellar ataxia cases result from postinfectious allergic autoimmune reactions. Antineuronal antibodies were detected in patients following ınfections . Our case was thought to be acute cerebellar ataxia caused by PVB19 infection. To the best of our knowledge, case reports of acute cerebellar ataxia associated with PVB19 infection are rare. Further attempts are required to clarify the role of this virus in the development of acute cerebellar ataxia as about 30% of PVB19 infections in children. Keywords: acute cerebellar ataxia; erythema infectiosum;human parvovirus B19

Concomitant opsoclonus ataxia and limbic encephalitis as a result of dual anti‐Ri and anti‐Yo antibodies in uterine carcinosarcoma: A case report

AbstractBackgroundParaneoplastic syndromes have become increasingly recognized as causing a number of neurological symptoms that can herald the presence of malignancy. A number of these antibodies have been identified. Few cases report paraneoplastic syndromes resulting from the presence of multiple antibodies in a single tumor source.Case presentationHere, we describe a case of simultaneous opsoclonus ataxia and limbic encephalitis from two concurrent paraneoplastic antibodies, anti‐Ri and anti‐Yo, in the presence of diagnosed uterine carcinosarcoma. Anti‐Ri (anti‐neuronal nuclear antibody type 2 or ANNA‐2) and anti‐Yo (anti‐Purkinje cell cytoplasmic antibody type 1) antibodies are known to be associated with opsoclonus myoclonus and cerebellar degeneration syndromes, respectively. Anti‐Ri has also been associated with limbic encephalitis.ConclusionsThis is a unique description of both anti‐Ri and anti‐Yo paraneoplastic antibodies with correlating syndromes in uterine carcinosarcoma. Although paraneoplastic syndromes are widely recognized and described, they are rare; but, as evidenced by this case, it is possible to have multiple concomitant syndromes and antibodies.

A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability

BackgroundHereditary cerebellar ataxia constitutes a heterogeneous group of neurodegenerative disorders, occasionally accompanied by other neurological features. Genetic defects remain to be elucidated in approximately 40% of hereditary cerebellar ataxia cases...

Spinal and Nucleus Caudalis Dorsal Root Entry Zone Lesioning for Chronic Pain: Efficacy and Outcomes

The role for nucleus caudalis (NC) and spinal dorsal root entry zone (DREZ) lesioning in the management of chronic pain emanating from increased electrical activity in the dorsal horn of the spinal cord and brainstem remains largely uncharted. All patients who underwent NC and spinal DREZ lesioning by a single surgeon were identified and follow-up was obtained by telephone questionnaires. Patient demographics, surgical details, outcomes, and complications were critically reviewed for all patients identified. Of 83 patients identified, 53 (63.9%) were male. Indications for NC DREZ lesioning included trigeminal neuropathic pain (6), trigeminal deafferentation pain (3), glossopharyngeal or occipital neuralgia (3), post-herpetic neuralgia (3), and trauma (1); for spinal DREZ lesioning, indications included brachial plexus avulsion (20), post-herpetic neuralgia (19), spinal cord injury (11), phantom limb pain (8), pelvic pain (5), and complex regional pain syndrome (4). Pain relief was most significant among patients with trigeminal pain, traumatic brachial plexus avulsion injuries, spinal cord injury, and traumatic phantom limb pain. Mean pain reduction averaged 58.3% at a mean follow-up of 8.3 years. Complications included 3 cases of paresis, 3 cases of neuropathy/radiculopathy, 2 cases of ataxia, 3 general medical conditions (colitis, 2; atelectasis, 1), and 2 cases of persistent incisional site pain. Pain relief lasted an average of 4.3 years. Spinal and NC DREZ lesioning can provide effective relief in well-selected patients with intractable chronic pain conditions arising from trigeminal pain, spinal cord injury, brachial plexus avulsions, post-herpetic neuralgia, and phantom limb pain.

A Case of Ataxia and Dystonia in the Setting of a Renal Oncocytoma (P2.112)

A Case of Ataxia and Dystonia in the Setting of a Renal Oncocytoma (P2.112)

Functional analysis helps to define KCNC3 mutational spectrum in Dutch ataxia cases.

Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominantly inherited neurodegenerative disorder of the cerebellum caused by mutations in the voltage gated potassium channel KCNC3. To identify novel pathogenic SCA13 mutations in KCNC3 and to gain insights into the disease prevalence in the Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies. We identified 19 variants in KCNC3 including 2 non-coding, 11 missense and 6 synonymous variants. Two missense variants did not co-segregate with the disease and were excluded as potentially disease-causing mutations. We also identified the previously reported p.R420H and p.R423H mutations in our cohort. Of the remaining 7 missense variants, functional analysis revealed that 2 missense variants shifted Kv3.3 channel activation to more negative voltages. These variations were associated with early disease onset and mild intellectual disability. Additionally, one other missense variant shifted channel activation to more positive voltages and was associated with spastic ataxic gait. Whereas, the remaining missense variants did not change any of the channel characteristics. Of these three functional variants, only one variant was in silico predicted to be damaging and segregated with disease. The other two variants were in silico predicted to be benign and co-segregation analysis was not optimal or could only be partially confirmed. Therefore, we conclude that we have identified at least one novel pathogenic mutation in KCNC3 that cause SCA13 and two additionally potential SCA13 mutations. This leads to an estimate of SCA13 prevalence in the Netherlands to be between 0.6% and 1.3%.

Acute cerebellar ataxia in a young woman: Wernicke’s encephalopathy?

Wernicke’s encephalopathy (WE) is a rare but severe neurological syndrome caused by thiamine deficiency. According to the data of autopsy studies, the prevalence of WE in the general population varies from 0.4 to 2.8 per 100,000 population; the disease occurs many times more frequently in alcohol abusers than in people who lead a healthy lifestyle. These studies also showed that most cases of WE were diagnosed postmortem; less than 20% of patients with the disease were diagnosed in life. A healthy adult requires 1–2 mg of thiamine daily, depending on the carbohydrate intake. Body’s reserves of thiamine are only 30–50 mg so any malnutrition condition lasting more than 3–4 weeks can cause complete depletion of the vitamin’s stores. Classically, WE is characterized by the sudden onset of a typical triad of symptoms: an altered mental state, ophthalmoplegia, and ataxia. However, this clinical picture can be seen in only one-third of patients. The onset of the disease may sometimes look completely different: heart failure with hypotension and tachycardia; gastrointestinal symptoms (abdominal pain and nausea); hypothermia due to the involvement of the posterior hypothalamus; deafness affecting the thalamus; epileptic seizures in case of enhanced activity of the glutamatergic system. The paper describes a clinical case of acute cerebellar ataxia that is apparently caused by Wernicke’s encephalopathy in a young woman.

Case of subacute cerebellar ataxia with anti‐glutamic acid decarboxylase antibodies in cerebrospinal fluid, but not in serum

AbstractA 67‐year‐old woman presented with dysarthria and trunk and limb ataxia, which progressed in a subacute manner. Anti‐glutamic acid decarboxylase antibodies were negative in the serum, but were detected in the cerebrospinal fluid. Steroid pulse therapy was administered on the suspicion that the presence of anti‐glutamic acid decarboxylase antibodies in the cerebrospinal fluid might be associated with cerebellar ataxia. Treatment resulted in a marked improvement in clinical symptoms, leading to a diagnosis of anti‐glutamic acid decarboxylase antibody‐positive cerebellar ataxia. The outcome showed that measuring anti‐glutamic acid decarboxylase antibodies levels in the cerebrospinal fluid is important, even when levels are negative in the serum.